Particle sampling systems and methods for robotic controlled manufacturing barrier systems

ABSTRACT

Provided herein are systems and methods allowing for automated sampling and/or analysis of controlled environments, for example, to determine the presence, quantity, size, concentration, viability, species or characteristics of particles within the environment. The described systems and methods may utilize robotics or automation or remove some or all of the collection or analysis steps that are traditionally performed by human operators. The methods and systems described herein are versatile and may be used with known particle sampling and analysis techniques and particle detection devices including, for example, optical particle counters, impingers and impactors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalPatent Application Nos. 62/768,365 filed Nov. 16, 2018 and 62/831,343filed Apr. 9, 2019, each of which is hereby incorporated by reference tothe extent not inconsistent herewith.

BACKGROUND OF INVENTION

This invention is in the field of manufacturing barrier systems. Thisinvention relates generally to systems and methods for robotic samplingand counting systems for sampling particles from fluids in controlledenvironments.

In sterile processing, aseptic manufacturing, and cleanroom environmentsin a number if industries such as pharmaceuticals, biopharmaceuticals,parenteral drugs and medical devices, and microfabrication among others,maintaining operations under stringent specifications for particulatematter and biological load is required.

In at least some known sterile, aseptic, or cleanroom environments,humans must be present in the environment to perform certain operations.For barrier systems, humans may be required to operate machines,manipulate objects, and otherwise interact with what is positionedinside the barrier system. Humans being present in such environmentsincreases the risk of particulate and biological contamination levels.Increasingly, controlled environment systems are moving towardsautomated or robotic systems in order to limit or eliminate humaninteraction. However, many applications requiring controlledenvironments also require or utilize environmental sampling to ensurethat viable and non-viable particles and/or organisms remain below thedesired levels.

As requirements for lower viable and non-viable particle concentrationsincrease because of increased quality standards and governmentalregulatory requirements there is a need for advancement in samplingtechnology in order to reduce false positives and reduce the risk ofoutside contamination from human interactions within the controlledenvironment.

It can be seen from the foregoing that there remains a need in the artfor particle collection, analysis, and characterization systems forsampling and collecting particles and/or organisms from controlledenvironments with reduced human interaction in order to reduce the riskof further contamination. These systems may include collection anyanalysis of particles within components of a robotic restricted accessbarrier system or other automated controlled environmental processes.

SUMMARY OF THE INVENTION

Provided herein are systems and methods allowing for automated samplingand/or analysis of controlled environments, for example, to determinethe presence, quantity, size, concentration, viability, species orcharacteristics of particles within the environment. The describedsystems and methods may utilize robotics or automation or remove some orall of the collection or analysis steps that are traditionally performedby human operators. The methods and systems described herein areversatile and may be used with known particle sampling and analysistechniques and devices including, for example, optical particlecounters, impingers and impactors.

The provided systems and methods may be useful within controlledenvironments utilizing a robotic system, for example, roboticallycontrolled restricted access barrier system (RABS) and positive pressureisolator systems. These systems and methods allow for integration with asampler and/or analyzer in the controlled environment to position,connect, sample and/or analyze the environmental conditions within thecontrolled environment with little or no human contact, reducing therisk of contamination from particles or organisms present on operators.The described systems and methods may also allow for roboticsterilization of the environment or sampling components to furtherreduce or eliminate the risk of contamination.

In one aspect, provided is a system for detecting particles in a fluid,the system comprising a particle detection device and a roboticmanipulator system. The particle detection device may comprise an inletfor receiving a particle-containing fluid, a sampling region fordetecting particles in the fluid, and an outlet for discharging thefluid. The sampling region is in fluid communication with the inlet. Theoutlet is in fluid communication with the sampling region. The roboticmanipulator system is configured to perform at least one of thefollowing steps: transport the particle detection device to the samplinglocation; remove the particle detection device from the samplinglocation; and regulate a flow of fluid through the particle detectiondevice.

In some embodiments, the particle detection device is an opticalparticle counter. In some embodiments, the optical particle counter is ascattered light particle counter, a light extinction optical particlecounter or a fluorescent optical particle counter. In some embodiments,the particle detection device is an impinger or a sampling cyclone. Insome embodiments, the particle detection device is an impactor

In some embodiments, the system may comprise a flow system for flowingthe fluid through the particle detection device. In some embodiments,the system may comprise a sterilization system for sterilizing all orpart of the particle detection device. In some embodiments, thesterilization system utilizes vaporized hydrogen peroxide, chlorinedioxide, ethylene oxide, moist heat or dry heat to sterilize theparticle detection device. In some embodiments, the robotic manipulatorsystem is configured to transport the particle detection device to thesterilization system. In some embodiments, impactor base having aplurality of grooves provided on an outer surface to interface with aworking end of the robotic manipulator system.

In some embodiments, the impactor comprises an impactor base having oneor more features to allow stacking of a plurality of the impactors. Insome embodiments, at least a portion of the impactor is transparent. Insome embodiments, the robotic manipulator system comprises an opticaldetector or an imaging device.

In some embodiments, the robotic manipulator system is configured toexpose the inlet of the particle detection device to the fluid. In someembodiments, the robotic manipulator system is configured to collectparticles from the particle detection device. In some embodiments, therobotic manipulator system is configured to operate the particledetection device in the absence of physical contact of the particledetection device by a user.

In some embodiments, the impactor includes a collection surfacecomprising a growth medium for receiving biological particles in thefluid, wherein the robotic manipulator system is configured fortransporting the impactor to the sterilization system in a fullyassembled configuration for sterilizing the impactor, and wherein thegrowth medium is present within the impactor during sterilizationthereof.

In some embodiments, the robotic manipulator system is configured toconnect the particle detection device to the flow system. In someembodiments, the robotic manipulator system is configured to open theinlet to allow for fluid flow into the particle detection device. Insome embodiments, the particle detection device comprises a cover forenclosing the inlet, and the robotic manipulator system is configured toremove the cover to allow for fluid to enter the inlet. In someembodiments, the robotic manipulator system is configured to replace thecover to stop the fluid from entering the inlet. In some embodiments,the robotic manipulator system is configured to close the inlet to stopfluid flow into the particle detection device.

In some embodiments, the flow system is located within a cleanroom oraseptic environment, and the robotic manipulator system is configured tosample the particles from the fluid in the absence of a user beingphysically present in the cleanroom or aseptic environment. In someembodiments, the robotic manipulator system is located inside of thecleanroom or aseptic environment. In some embodiments, the roboticmanipulator system is configured to stack and unstack a plurality ofimpactors.

In one aspect, a method for detecting particles in a fluid is provided.The method may comprise the steps of: exposing the inlet of a particledetection device to a particle-containing fluid; flowing theparticle-containing fluid into the inlet; directing the fluid through asampling region of the device; and discharging the fluid through anoutlet of the device. The exposing step and/or the flowing step may beperformed by a robotic manipulator system. The method may comprisesterilizing the particle detection device via the robotic manipulatorsystem. In some embodiments, the method may include transporting theparticle detection device, via the robotic manipulator system, to asterilization location for the sterilizing step. After the sterilizingstep, the method may include transporting the particle detection device,via the robotic manipulator system, to a sampling location.

In some embodiments, the particle detection device comprises animpactor, and the sterilizing step comprises sterilizing the impactor ina fully assembled configuration. In some embodiments, a collectionsurface of the impactor remains enclosed during sterilization. In someembodiments, the sterilizing step comprises treating the impactor withvaporized hydrogen peroxide.

In some embodiments, at least some of the particles in the fluid to besampled are biological particles and the method includes culturing atleast a portion of the biological particles received by the impactor,wherein the culturing occurs inside the impactor in a fully assembledimpactor. In some embodiments, the method includes optically detectingcultured biological particles via the robotic manipulator system.

In some embodiments, the method includes characterizing the culturedbiological particles via optical detection or imaging performed by therobotic manipulator system. In some embodiments, the method includesdetermining a viability, an identity or both of microorganisms in thecultured biological particles. In some embodiments, the determining stepis performed by the robotic manipulator system.

In some embodiments, the flowing step comprises regulating a flow rateof the fluid via the robotic manipulator system. In some embodiments themethod includes, prior to the flowing step, connecting the particledetector to a flow system. In some embodiments, the impactor is asingle-use device. In some embodiments, the method includes collectingat least a portion of the particles that flow into the inlet. In someembodiments, the collecting step is performed by the robotic manipulatorsystem.

In some embodiments, the robotic manipulator system comprises an imagingdevice; and wherein the characterizing step is performed via the imagingdevice. In some embodiments, the fluid originates and/or terminates in acleanroom or aseptic environment, and the method is performed in theabsence of a user being physically present in the cleanroom or asepticenvironment. In some embodiments, the exposing step and the flowing stepare performed by the robotic manipulator system.

In an aspect, provided is a system for detecting particles in a fluid,the system comprising: i) an optical particle counter comprising: a) aflow chamber for flowing a fluid containing particles along a flowdirection through a beam of electromagnetic radiation, b) an opticalsource, in optical communication with the flow chamber, for providingthe beam of electromagnetic radiation; and c) an optical collectionsystem for collecting and directing at least a portion ofelectromagnetic radiation onto a photodetector; wherein thephotodetector produces an electric signal characteristic of the numberand/or size of the particles detected; ii) a flow system for flowing atleast a portion of the fluid through the flow chamber of the opticalparticle counter to interact with the beam of electromagnetic radiation;and iii) a robotic control system configured to direct movements for atleast one of: providing the optical particle counter to a samplinglocation; transporting the optical particle counter to and from thesampling location; and regulating a flow rate of the fluid through theflow chamber of the optical particle counter. The optical particlecounter may be a scattered light particle counter, a light extinctionoptical particle counter or a fluorescent optical particle counter.

In an aspect, provided is a system for sampling particles from a fluid,the system comprising: i) an impinger or a sampling cyclone; ii) a flowsystem for flowing at least a portion of the fluid through the impingeror the sampling cyclone to facilitate receiving at least a portion ofthe particles in the fluid by the impinger or the sampling cyclone; andiii) a robotic control system configured to direct movements of at leastone of: providing the impinger or the sampling cyclone to a samplinglocation; transporting the impinger or the sampling cyclone to and fromthe sampling location; and regulating a flow rate of the fluid throughthe impinger or the sampling cyclone.

In an aspect, provided is a system for sampling particles from a fluid,the system comprising: i) an impactor comprising: a) a sampling headcomprising one or more intake apertures for sampling a fluid flowcontaining particles; and b) an impactor base operationally connected toreceive at least a portion of the fluid flow from the sampling head; theimpactor base comprising an impact or collection surface for receivingat least a portion of the particles in the fluid flow and an outlet forexhausting the fluid flow; wherein the sampling head and the impactorbase are integrated components that engage to enclose the impactsurface; and wherein the impactor provides for sampling of the particlesand growth of biological particles received on the impact surfacewithout disengaging the sampling head and the impactor base; ii) a flowsystem for flowing at least a portion of the fluid through impactor tofacilitate receiving at least a portion of the particles in the fluid bythe impactor; and iii) a robotic control system configured to directmovements of at least one of: providing the impactor to a samplinglocation; transporting the impactor to and from the sampling location;and regulating a flow rate of the fluid through the impactor device.

The systems described herein may further comprise a sterilization systemfor sterilizing the optical particle counter, the impactor, the impingeror the sampling cyclone. The sterilization system may utilize vaporizedhydrogen peroxide, chlorine dioxide, ethylene oxide, moist heat and dryheat. The robotic control system may be further configured fortransporting the optical particle counter, the impactor, the impinger orthe sampling cyclone to the sterilization system.

The impactor collection surface may be configured to receive and capturebiological particles. The sampling head and the impactor base may engageto entirely enclose the collection surface, including for example,engaging via a substantially airtight seal. The sampling head and theimpactor base may each independently comprise a polymer material. Theimpactor base may have a plurality of grooves provided on an outersurface to allow for effective handling of the impactor by the roboticcontrol system. The impactor base may have one or more features to allowfor effective stacking of a plurality of the impactors. At least aportion of the impactor base, sampling head, or both may be opticallytransparent.

The collection surface may comprise a growth medium for receivingbiological particles in the fluid. The robotic control system mayfurther comprise an optical detector or an imaging device. The roboticcontrol system may be further configured to expose the optical particlecounter, the impactor, the impinger, the sampling cyclone and/or thecollection surface to the fluid. The robotic control system may befurther configured to collect particles from the optical particlecounter, the impactor, the impinger, the sampling cyclone and/or thecollection surface. The robotic control system may be further configuredto sample the particles from the fluid in the absence of a userphysically contacting the optical particle counter, the impactor, theimpinger or the sampling cyclone.

The impactor and/or the collection surface may comprise a growth mediumfor receiving biological particles in the fluid; wherein the roboticcontrol system is further configured for transporting the particlesampling or counting device to the sterilization system in a fullyassembled configuration for sterilizing the particle sampling orcounting device; and wherein the growth medium is present within theparticle sampling or counting during sterilization thereof.

The robotic control system may be further configured to connect theoptical particle counter, the impactor, the impinger or the samplingcyclone to the flow system. The optical particle counter, the impactor,the impinger or the sampling cyclone may further comprise an inlet forreceiving the at least a portion of the fluid under flow; wherein therobotic control system is further configured to open the inlet to allowfor fluid flow into the optical particle counter, the impactor, theimpinger or the sampling cyclone.

The optical particle counter, the impactor, the impinger or the samplingcyclone may further comprise a cover for enclosing the optical particlecounter, the impactor, the impinger or the sampling cyclone; wherein therobotic control system is further configured to remove the cover toallow for fluid to contact the optical particle counter, the impactor,the impinger or the sampling cyclone. The robotic control system may befurther configured to close the inlet to stop fluid flow into theoptical particle counter, the impactor, the impinger or the samplingcyclone. The robotic control system may be further configured to replacethe cover to stop fluid from contacting the optical particle counter,the impactor, the impinger or the sampling cyclone.

The flow system may be integrated within a cleanroom or asepticenvironment, and wherein the robotic control system is furtherconfigured to sample the particles from the fluid under flow in theabsence of a user being physically present in the cleanroom or asepticenvironment. The robotic control system may be located inside of thecleanroom or aseptic environment, outside of the cleanroom or asepticenvironment or partially located both inside and outside of thecleanroom or aseptic environment. The systems described herein mayfurther comprise a plurality of impactors or impingers, wherein therobot controller is further configured to direct movements of the robotfor stacking and unstacking the impactors or impingers.

In an aspect, provided in a method for detecting particles in a fluid,the method comprising the steps of: i) providing an optical particlecounter comprising: a) a flow chamber for flowing a liquid containingparticles along a flow direction through a beam of electromagneticradiation, b) an optical source, in optical communication with the flowchamber, for providing the beam of electromagnetic radiation; and c) anoptical collection system for collecting and directing at least aportion of electromagnetic radiation onto a photodetector; wherein thephotodetector produces an electric signal characteristic of the numberand/or size of the particles detected; ii) flowing at least a portion ofthe fluid through the flow chamber of the optical particle counter; andiii) determining the number and/or size of the particles detected basedon the electric signal; wherein at least one of the providing step orthe flowing step is performed by a system configured for roboticcontrol.

In an aspect, provided is a method for sampling particles from a fluid,the method comprising the steps of: i) providing an impinger or asampling cyclone; ii) flowing at least a portion of the fluid throughthe impinge or sampling cyclone; and iii) receiving at least a portionof the particles in the fluid in the impinger or sampling cyclone;wherein at least one of the providing step, flowing step, and receivingstep is performed by a system configured for robotic control.

In an aspect, provided is a method for sampling particles from a fluid,the method comprising the steps of: i) providing an impactor comprising:a) a sampling head comprising one or more intake apertures for samplinga fluid flow containing particles; and b) an impactor base operationallyconnected to receive at least a portion of the fluid flow from thesampling head; the impactor base comprising an impact or collectionsurface for receiving at least a portion of the particles in the fluidflow and an outlet for exhausting the fluid flow; wherein the samplinghead and the impactor base are integrated components that engage toenclose the impact surface; and wherein the impactor provides forsampling of the particles and growth of biological particles received onthe impact surface without disengaging the sampling head and theimpactor base; ii) flowing at least a portion of the fluid through thesampling head of the impactor; and iii) receiving at least a portion ofthe particles in the fluid on the impact surface of the impactor base;wherein at least one of the providing step, flowing step, and receivingstep is performed by a system configured for robotic control.

In an aspect, provided is a method for sampling particles from a fluidcomprising: i) providing a particle sampling or counting device; ii)flowing at least a portion of the fluid through the particle sampling orcounting device; and iii) receiving at least a portion of the particles(4) in the fluid (6) in the particle counting or sampling device;wherein at least one of the providing step, flowing step, and receivingstep is performed by a system configured for robotic control. The fluidmay be the gas in a controlled environment such as air or an inert gas.The particle sampling or counting device may comprise an impactor, animpinger, a sampling cyclone and/or an optical particle counter.

The provided method may further comprise a step of sterilizing at leasta portion of the system configured for robotic control, for example,comprising a step of sterilizing the particle sampling or countingdevice. The particle sampling or counting device may be sterilized in afully assembled configuration. The providing step may comprisepositioning the particle sampling or counting device to a location forthe sterilizing step by the system configured for robotic control. Theproviding step may comprise positioning the particle sampling orcounting device for receiving the particles after the sterilizing stepby the system configured for robotic control.

The described particle sampling or counting device may comprise: a) acollection surface configured to receive at least a portion of theparticles in the fluid; b) a sampling head comprising one or more inletsfor receiving at least a portion of the fluid under flow; and c) a baseoperationally connected to the sampling head to receive at least aportion of the sampled fluid from the sampling head, wherein the basecomprises: the collection surface; and a fluid outlet; wherein thesampling head and the base are integrated components that engage toenclose the collection surface; and wherein the flowing step comprisescontacting at least a portion of the fluid with the collection surface.

The sampling head and base may engage to entirely enclose the collectionsurface, for example, via a substantially airtight seal. The samplinghead and base may each independently comprise a polymer material. Thebase may have a plurality of grooves provided on an outer surface of thebase to allow for effective handling of the particle sampling orcounting device by the system configured for robotic control. The basemay have one or more features to allow for effective stacking of aplurality of the particle sampling or counting devices.

At least a portion of the base, the sampling head, or both may beoptically transparent. The provided method may further comprise a stepof sterilizing the particle sampling or counting device, wherein thecollection surface remains enclosed during sterilization, for example,to protect a growth media for capturing biological particles such asagar. The collection surface may comprise a growth medium for receivingbiological particles.

The provided method may further comprise a step of sterilizing theparticle sampling or counting device in a fully assembled configuration,wherein the collection surface remains enclosed by the sampling head andbase during sterilization. The sterilizing step may be performed bytreating the fully assembled and enclosed particle sampling or countingdevice with at least one of: vaporized hydrogen peroxide, chlorinedioxide, ethylene oxide, moist heat, and dry heat.

The provided method may further comprise a step of culturing at least aportion of the biological particles received by the growth medium. Theculturing step may allow for optical detection of the biologicalparticles. The culturing step may be carried out without disassemblingthe fully assembled particle sampling or counting device.

The provided method may further comprise a step of characterizing atleast a portion of the grown biological particles by visualization,optical detection, molecular detection (e.g., techniques utilizingpolymerase chain reaction (PCR) for biological materials) and/orimaging. The culturing step, the characterizing step, or both may becarried out by the system configured for robotic control. The providedmethod may further comprise a step of determining the presence of, theviability, an identity or both of microorganisms in the grown biologicalparticles. The determining step may be carried out by the systemconfigured for robotic control.

The described providing step may comprise exposing the particlecollection or sampling device to the fluid using the system configuredfor robotic control. The providing step may comprise exposing thecollection surface of the particle collection or sampling device to thefluid using the system configured for robotic control. The flowing stepmay comprise regulating a flow rate of the fluid by the systemconfigured for robotic control.

The provided method may further comprise a step of removing a cover ofthe particle sampling or counting device or opening an inlet of theparticle counting or sampling device by the system configured forrobotic control. The provided method may further comprise a stepconnecting the particle sampling or counting device to a flow system toallow for flowing the fluid by the system configured for roboticcontrol.

The provided method may further comprise a step of replacing a cover ofthe particle sampling or counting device or closing an inlet of theparticle counting or sampling device by the system configured forrobotic control. The provided method may further comprise a step ofdisconnecting the particle sampling or counting device from a flowsystem to stop flow of the fluid by the system configured for roboticcontrol. The particle sampling or counting device may be a single use(e.g. disposable) particle counting or sampling device.

The provided method may further comprise a step of collecting at least aportion of the particles received by the particle sampling or countingdevice and/or the collection surface. The described collecting step maybe performed by the system configured for robotic control. The systemconfigured for robotic control may comprise an imaging device.

The provided method may further comprise a step of characterizing theparticles performed by the imaging device. The characterizing step maycomprise, for example, determining a chemical composition of theparticles or determining a particle size distribution of the particles.

The provided method may be performed in the absence of a user physicallycontacting the particle sampling or counting device. The fluid mayoriginate and/or terminate in a cleanroom or aseptic environment; andwherein the method is performed in the absence of a user beingphysically present in the cleanroom or aseptic environment. Each of theproviding step, flowing step, and/or receiving step, may be performed bythe system configured for robotic control.

In an aspect, provided is a system for sampling particles from a fluid,the system comprising: a) a particle sampling or counting device; b) aflow system for flowing at least a portion of the fluid through theparticle sampling or counting device to facilitate receiving at least aportion of the particles in the fluid by the particle sampling orcounting device; c) a robot; and d) a robot controller for controllingthe robot, wherein the robot controller is configured to directmovements of the robot for at least one of: i) providing the particlesampling or counting device to a sampling location; ii) transporting theparticle sampling or counting device to and from the sampling location;and iii) regulating a flow rate of the fluid through the particlesampling or counting device.

The particle sampling or counting device may be an impactor, animpinger, a sampling cyclone and/or an optical particle counter. Theprovided system may further comprise a sterilization system forsterilizing the particle sampling or counting device. The sterilizationsystem may utilize at least one of: vaporized hydrogen peroxide,chlorine dioxide, ethylene dioxide, moist heat, and dry heat. Therobotic controller may be further configured to direct movements of therobot for transporting the particle sampling or counting device to orfrom the sterilization system.

The particle sampling or counting device may comprise: A) a collectionsurface configured to receive the at least a portion of the particles inthe fluid; B) a sampling head comprising one or more inlets for samplingat least a portion of the fluid under flow; and C) a base operationallyconnected to the sampling head to receive at least a portion of thesampled fluid from the sampling head, wherein the base comprises: acollection surface; and a fluid outlet, wherein the sampling head andthe base are integrated components that engage to enclose the collectionsurface; and wherein the flow system is configured to contact at least aportion of the fluid under flow with the collection surface.

The sampling head and the base may engage to entirely enclose thecollection surface. The sampling head and the base may engage via asubstantially airtight seal. The sampling head and the base may eachindependently comprise a polymer material. The sampling head or the basemay have a plurality of grooves provided on an outer surface to allowfor effective handling of the particle sampling or counting device bythe robot. The sampling head or the base may have one or more featuresto allow for effective stacking of a plurality of the particle samplingor counting devices. At least a portion of each of the base, thesampling head, or both may be optically transparent.

The collection surface may comprise a growth medium (e.g. agar) forreceiving biological particles in the fluid under flow. The robot mayfurther comprise an optical detector or an imaging device. The robotcontroller may be further configured to direct movements of the robotfor exposing the particle sampling or counting device and/or collectionsurface to the fluid. The robot controller may be further configured todirect movements of the robot to collect particles from the particlesampling or counting device and/or collection surface. The robotcontroller may be further configured to direct movements of the robot tosample the particles from the fluid in the absence of a user physicallycontacting the particle sampling or counting device.

The provided system may be configured such that the particle sampling orcounting device and/or the collection surface comprises a growth mediumfor receiving biological particles in the fluid; wherein the robotcontroller is further configured to direct movements of the robot fortransporting the particle sampling or counting device to thesterilization system in a fully assembled configuration for sterilizingthe particle sampling or counting device; and wherein the growth mediumis present within the particle sampling or counting device duringsterilization thereof.

The robot controller may be further configured to direct movements ofthe robot to connect the particle sampling or counting device to theflow system. The particle sampling or counting device may furthercomprise a fluid inlet for receiving at least a portion of the fluidunder flow; wherein the robot controller is further configured to directmovements of the robot to open the inlet to allow for fluid flow intothe particle sampling or counting device. The particle sampling orcounting device may further comprise a cover for enclosing the particlecounting or sampling device; wherein the robot controller is furtherconfigured to direct movements of the robot to remove the cover to allowfor fluid to contact the particle sampling or counting device.

The robot controller may be further configured to direct movements ofthe robot to close the inlet to stop fluid flow into the particlesampling or counting device. The robot controller may be furtherconfigured to direct movements of the robot to replace the cover to stopfluid from contacting the particle sampling or counting device.

The flow system may be integrated within a cleanroom or asepticenvironment, and wherein the robot controller is further configured todirect movements of the robot to sample the particles from the fluidunder flow in the absence of a user being physically present in thecleanroom or aseptic environment. The robot may be located inside of thecleanroom or aseptic environment and the robot controller is locatedoutside of the cleanroom or aseptic environment. The provided system mayfurther comprise a plurality of particle sampling or counting devices,wherein the robot controller is further configured to direct movementsof the robot for stacking and unstacking the particle sampling orcounting devices.

Without wishing to be bound by any particular theory, there may bediscussion herein of beliefs or understandings of underlying principlesrelating to the devices and methods disclosed herein. It is recognizedthat regardless of the ultimate correctness of any mechanisticexplanation or hypothesis, an embodiment of the invention cannonetheless be operative and useful.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flowchart of a method for sampling particles from a fluid inaccordance with one embodiment of the disclosure.

FIG. 2 is a schematic diagram of a system for sampling particles from afluid which may be used to perform the method of FIG. 1 in accordancewith one embodiment of the disclosure.

FIG. 3 is a schematic diagram of an exemplary impinger during use in thesystem of FIG. 2.

FIG. 4 is a flowchart of an example of the method shown in FIG. 1 inaccordance with another embodiment of the disclosure.

FIG. 5 shows a perspective view of an exemplary impactor of the presentinvention.

FIG. 6 shows a sectional view of impactor of FIG. 2.

FIG. 7 is an exploded view of the impactor of FIGS. 5 and 6, whereincomponents of the device are spatially separated for clarity.

FIG. 8 shows a perspective view of impactor of the present invention.

FIG. 9 is a flowchart of an example of the method shown in FIG. 1 inaccordance with yet another embodiment of the disclosure.

FIG. 10 is a flowchart of an example of the method shown in FIG. 1 inaccordance with still another embodiment of the disclosure.

FIG. 11 is a flowchart of an example of the method shown in FIG. 1 inaccordance with another embodiment of the disclosure.

FIG. 12 is a flowchart of an example of the method shown in FIG. 1 inaccordance with yet another embodiment of the disclosure.

FIG. 13 is a flowchart of an example of the method shown in FIG. 1 inaccordance with still another embodiment of the disclosure.

FIG. 14 provides an example of an optical particle counter which is usedin some embodiments of the present invention.

FIG. 15 provides an example of a robotic manipulator in accordance withone embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

In the following description, numerous specific details of the devices,device components and methods of the present invention are set forth inorder to provide a thorough explanation of the precise nature of theinvention. It will be apparent, however, to those of skill in the artthat the invention can be practiced without these specific details.

In general, the terms and phrases used herein have their art-recognizedmeaning, which can be found by reference to standard texts, journalreferences and contexts known to those skilled in the art. The followingdefinitions are provided to clarify their specific use in the context ofthe invention.

“Operably connected,” “operatively coupled,” “operatively connected,”and “operatively coupled” refers to a configuration of elements, whereinan action or reaction of one element affects another element, but in amanner that preserves each element's functionality. The connection maybe by a direct physical contact between elements. The connection may beindirect, with another element that indirectly connects the operablyconnected elements. The term also refers to two or morefunctionally-related components being coupled to one another forpurposes of flow of electric current and/or flow of data signals. Thiscoupling of the two or more components may be a wired connection and/ora wireless connection. The two or more components that are so coupledvia the wired and/or wireless connection may be proximate one another(e.g., in the same room or in the same housing) or they may be separatedby some distance in physical space (e.g., in a different building).

“Particles” refers to small objects which are often regarded ascontaminants. A particle can be any material created by the act offriction, for example, when two surfaces come into mechanical contactand there is mechanical movement. Particles can be composed ofaggregates of material, such as dust, dirt, smoke, ash, water, soot,metal, minerals, or any combination of these or other materials orcontaminants. “Particles” may also refer to biological particles, forexample, viruses, prions, spores and microorganisms including bacteria,fungi, archaea, protists, other single cell microorganisms andspecifically those microorganisms having a size on the order of <1-15μm. A particle may refer to any small object which absorbs, occludes orscatters light and is thus detectable by an optical particle counter. Asused herein, “particle” is intended to be exclusive of the individualatoms or molecules of a carrier fluid, for example water molecules,process chemical molecules, oxygen molecules, helium atoms, nitrogenmolecules, etc. Some embodiments of the present invention are capable ofdetecting, sizing, and/or counting particles comprising aggregates ofmaterial having a size greater than 10 nm, 20 nm, 30 nm, 50 nm, 100 nm,500 nm, 1 μm or greater, or 10 μm or greater. Specific particles includeparticles having a size selected from 20 nm to 50 nm, 50 nm to 50 μm, asize selected from 100 nm to 10 μm, or a size selected from 500 nm to 5μm.

The expression “sampling a particle” broadly refers to collection ofparticles in a fluid flow, for example, from an environment undergoingmonitoring. Sampling in this context includes transfer of particles in afluid flow to an impact surface, for example, the receiving surface of agrowth medium. Alternatively, sampling may refer to passing particles ina fluid through a particle analysis region, for example, for opticaldetection and/or characterization. Sampling may refer to collection ofparticles having one or more preselected characteristics, such as size(e.g., cross sectional dimension such as diameter, effective diameter,etc.), particle type (biological or nonbiological, viable or nonviable,etc.) or particle composition. Sampling may optionally include analysisof collected particles, for example, via subsequent optical analysis,imaging analysis or visual analysis. Sampling may optionally includegrowth of viable biological particles, for sample, via an incubationprocess involving a growth medium. A sampler refers to a device forsampling particles.

“Impactor” refers to a device for sampling particles. In someembodiments, an impactor comprises a sample head including an inlet,e.g., one or more intake apertures, for sampling a fluid flow containingparticles, whereby, in a sampling region of the impactor, at least aportion of the particles are directed onto an impact surface forcollection, such as the receiving surface of a growth medium (e.g.,culture medium such as agar, broth, etc.) or a substrate such as afilter. Impactors of some embodiments, provide a change of direction ofthe flow after passage through the intake apertures, wherein particleshaving preselected characteristics (e.g., size greater than a thresholdvalue) do not make the change in direction and, thus, are received bythe impact surface.

“Impinger” refers to an enclosed sampling device designed to contain afluid to capture particles from an environmental fluid due to aninteraction between the particles and the impinger fluid. The impingermay include an inlet, a sampling region where the particles interactwith the fluid, and an outlet. For example, an impinger may contain aliquid allowing for particles in a vapor to become suspended within theliquid due to flow of the vapor over the surface or through the liquidmedia. Impingers may use water, condensates, polar fluids, non-polarfluids and solvents.

“Cyclone sampler” refers to a sampling device that directs the flow of afluid though an inlet, into a vortex or cyclone within a sampling regionof the sampler to force particles within the flow towards the outside ofthe sampler where they are captured, for example, due to the force ofthe fluid flow or within a sampling media or filtration system.

The expression “detecting a particle” broadly refers to sensing,identifying the presence of and/or characterizing a particle. In someembodiments, detecting a particle refers to counting particles. In someembodiments, detecting a particle refers to characterizing and/ormeasuring a physical characteristic of a particle, such as diameter,cross sectional dimension, shape, size, aerodynamic size, or anycombination of these. A particle counter is a device for counting thenumber of particles in a fluid or volume of fluid, and optionally mayalso provide for characterization of the particles, for example, on thebasis of size (e.g., cross sectional dimension such as diameter oreffective diameter), particle type (e.g. biological or nonbiological),or particle composition. An optical particle counter is a device thatdetects particles by measuring scattering, emission, extinction orabsorbance of light by particles.

“Flow direction” refers to an axis parallel to the direction the bulk ofa fluid is moving when a fluid is flowing. For fluid flowing through astraight flow cell, the flow direction is parallel to the path the bulkof the fluid takes. For fluid flowing through a curved flow cell, theflow direction may be considered tangential to the path the bulk of thefluid takes.

“Optical communication” refers to an orientation of components such thatthe components are arranged in a manner that allows light orelectromagnetic radiation to transfer between the components.

“Fluid communication” refers to the arrangement of two or more objectssuch that a fluid can be transported to, past, through or from oneobject to another. For example, in some embodiments two objects are influid communication with one another if a fluid flow path is provideddirectly between the two objects. In some embodiments, two objects arein fluid communication with one another if a fluid flow path is providedindirectly between the two objects, such as by including one or moreother objects or flow paths between the two objects. For example, in oneembodiment, the following components of a particle impactor are in fluidcommunication with one another: one or more intake apertures, an impactsurface, a fluid outlet, a flow restriction, a pressure sensor, aflow-generating device. In one embodiment, two objects present in a bodyof fluid are not necessarily in fluid communication with one anotherunless fluid from the first object is drawn to, past and/or through thesecond object, such as along a flow path.

“Flow rate” refers to an amount of fluid flowing past a specified pointor through a specified area, such as through intake apertures or a fluidoutlet of a particle impactor. In one embodiment, a flow rate refers toa mass flow rate, i.e., a mass of the fluid flowing past a specifiedpoint or through a specified area. In one embodiment, a flow rate is avolumetric flow rate, i.e., a volume of the fluid flowing past aspecified point or through a specified area.

“Pressure” refers to a measure of a force exhibited per unit area. In anembodiment, a pressure refers to a force exhibited by a gas or fluid perunit area. An “absolute pressure” refers to a measure of the pressureexerted by a gas or fluid per unit area as referenced against a perfectvacuum or volume exerting zero force per unit area. Absolute pressure isdistinguished from a “differential pressure” or “gauge pressure”, whichrefers to a relative change or difference in force exhibited per unitarea in excess of or relative to a second pressure, such as an ambientpressure or atmospheric pressure.

“Polymer” refers to a macromolecule composed of repeating structuralunits connected by covalent chemical bonds or the polymerization productof one or more monomers, often characterized by a high molecular weight.The term polymer includes homopolymers, or polymers consistingessentially of a single repeating monomer subunit. The term polymer alsoincludes copolymers, or polymers consisting essentially of two or moremonomer subunits, such as random, block, alternating, segmented,grafted, tapered and other copolymers. Useful polymers include organicpolymers or inorganic polymers that may be in amorphous, semi-amorphous,crystalline or partially crystalline states. Crosslinked polymers havinglinked monomer chains are particularly useful for some applications.Polymers useable in the methods, devices and components include, but arenot limited to, plastics, elastomers, thermoplastic elastomers,elastoplastics, thermoplastics and acrylates. Exemplary polymersinclude, but are not limited to, acetal polymers, biodegradablepolymers, cellulosic polymers, fluoropolymers, nylons, polyacrylonitrilepolymers, polyamide-imide polymers, polyimides, polyarylates,polybenzimidazole, polybutylene, polycarbonate, polyesters,polyetherimide, polyethylene, polyethylene copolymers and modifiedpolyethylenes, polyketones, poly(methyl methacrylate),polymethylpentene, polyphenylene oxides and polyphenylene sulfides,polyphthalamide, polypropylene, polyurethanes, styrenic resins,sulfone-based resins, vinyl-based resins, rubber (including naturalrubber, styrenebutadiene, polybutadiene, neoprene, ethylene-propylene,butyl, nitrile, silicones), acrylic, nylon, polycarbonate, polyester,polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyolefinor any combinations of these.

FIG. 1 is a flowchart of a method (2) for sampling particles (4) from afluid (6) in accordance with one embodiment of the disclosure. FIG. 2schematically shows an embodiment of an example robotic sampling andcounting system (8) for sampling particles (4) from fluid (6). In anexample, method (2) is implemented and performed, at least in part, bysystem (8).

Referring to FIGS. 1, 2, and 15, method (2) includes providing (10) aparticle sampling or counting device (12). Method (2) includes flowing(14) at least a portion of fluid (6) through particle sampling orcounting device (12), and receiving (16) at least a portion of particles(4) in fluid (6) in particle counting or sampling device (12). At leastone of: providing step (10), flowing step (14), and receiving step (16),is performed by a system configured for robotic control (18) (e.g., arobotic manipulator (20)). Alternatively, any combination of: providingstep (10), flowing step (14), and receiving step (16), are performed bysystem configured for robotic control (18). In another example, each of:providing step (10), flowing step (14), and receiving step (16), areperformed by system configured for robotic control (18).

Referring to FIGS. 2 and 15, system (8) includes one or more particlesampling or counting device(s) (12). System (8) includes a flow system(22) for flowing at least a portion of fluid (6) into and/or throughparticle sampling or counting device (12) to facilitate receiving atleast a portion of particles (4) in fluid (6) by the particle samplingor counting device (12). Flow system (22) includes a flow-regulatingvalve (3). Flow system (22) includes a sampling port (5) configured forflow communication with particle sampling or counting device (12).System (8) includes robotic manipulator (20) and a robot controller (24)for controlling robotic manipulator (20). Robot controller (24) isoperatively connected to robotic manipulator (20). Robotic manipulator(20) includes at least one robot arm (21) having one or more degrees offreedom of movement. Robot arm (21) includes at least one working end(27) configured for at least one of: gripping, moving, and/or otherwisemanipulating objects positioned inside system (8). Robot controller (24)is configured to direct movements (25) of robotic manipulator (20) forat least one of: positioning the particle sampling or counting device(12) in a sampling location (26), transporting particle sampling orcounting device (12) to and from sampling location (26), and regulatinga flow rate of the fluid (6) into and/or through the particle samplingor counting device (12).

In the example shown in FIGS. 2 and 15, system (8) is situated in aninterior (9) of an aseptic or cleanroom environment (13). Aseptic orcleanroom environment (13) includes a heating, ventilation, and airconditioning (HVAC) system (11). HVAC system (11) may include componentspositioned in either interior (9) or an exterior (15), or both, ofaseptic or cleanroom environment (13). HVAC system (11) receives asupply fluid (17) (e.g., air from exterior (15)) through at least onesupply duct (19). HVAC system (11) processes supply fluid (17) to, forinstance, regulate its temperature and/or flow rate, and/or reduceparticulate matter present in supply fluid (17). Fluid (6) exits HVACsystem (11) and flows into interior (9) of cleanroom or asepticenvironment (13) through at least one interior duct (29). Interiorduct(s) (29) deliver fluid (6) to various processing equipment (23)positioned in cleanroom or aseptic environment (13).

Example 1—Particle and Biological Contaminant Sampling or CountingDevices, or Viable/Non-Viable Particle Sampling Devices

In an example, particle sampling or counting device (12) is an impactor(28). Impactor (28) may be any of the devices disclosed in U.S. patentapplication Ser. No. 14/338,615, which is incorporated by referenceherein in its entirety. In another example, particle sampling orcounting device (12) is an impinger (30). In yet another example,particle sampling or counting device (12) is configured for use withcyclone-based methods. In still another embodiment, the particlesampling or counting device (12) is an optical particle counter (32). Instill another embodiment, the particle sampling or counting device (12)includes any combination of: impactor (28), impinger (30), opticalparticle counter (32), and device (12) configured for use withcyclone-based methods. In yet another embodiment, the particle samplingor counting device (12) includes each of: impactor (28), impinger (30),optical particle counter (32), and device (12) configured for use withcyclone-based methods.

FIG. 3 is a schematic diagram of an exemplary impinger (30) during usein system (8). Impinger (30) is filled at least partially with a liquid(31), which may be a liquid growth medium (72). An end of impinger (30)is configured to be fitted (e.g., by robot arm (21) of roboticmanipulator (20)) over an end of sampling port (5). Fluid (6) sampled byimpinger (30) flows into impinger (30). Liquid (31) contained insideimpinger (30) traps particles (4) present in fluid (6) for latercharacterization and/or analysis. After entrapment of particles (4) fromincoming fluid (6) flowing into impinger (30) from sampling port (5),fluid (6) continues to flow out of impinger (30) from a fluid outlet(54). Impinger (30) includes a cover (86) and a seal (56) providing anairtight and/or hermetically sealed operative coupling of cover (86) toimpinger (30) (e.g., to prevent contamination of liquid (31)).

Automated Sterilization

FIG. 4 is a flowchart of an example of method (2) for sampling particles(4) from a fluid (6) in accordance with another embodiment of thedisclosure. In the example, method (2) includes sterilizing (34) atleast a portion of system configured for robotic control (18). In theexample, method (2) includes sterilizing (36) particle sampling orcounting device (12). In method (2), the sterilizing step (36) includessterilizing particle sampling or counting device (12) in a fullyassembled configuration.

Referring to FIG. 2, system (8) includes a sterilization system (38) forsterilizing the particle sampling or counting device (12). In anexample, sterilization system (38) utilizes at least one of: vaporizedhydrogen peroxide, chlorine dioxide, ethylene dioxide, radiation, moistheat, and dry heat. Robot controller (24) is configured to directmovements (25) of robotic manipulator (20) for transporting particlesampling or counting device (12) to sterilization system (38).

In the example, providing step (10) of method (2) includes positioning(40) particle sampling or counting device (12) to a location (42) forthe sterilizing step (34 and/or 36) by system configured for roboticcontrol (18) (e.g., including, without limitation, robotic manipulator(20)). In the example, positioning (40) is performed in method (2) priorto the step of providing (10). Alternatively, positioning (40) isperformed in method (2) after the step of providing (10). In anotherexample, positioning (40) is performed in method (2) concurrently withthe step of providing (10). In the example, positioning (40) isperformed in method (2) prior to sterilizing (34 and/or 36).Alternatively, positioning (40) is performed in method (2) concurrentlywith sterilizing (34 and/or 36). In an example, providing step (10) ofmethod (2) includes positioning (44) particle sampling or countingdevice (12) for receiving (16) the particles (4) from the sterilizingstep (34 and/or 36) by system configured for robotic control (18).

Particle Collection Configuration

In an example, particle sampling or counting device (12) of system (8)is impactor (28). FIG. 5 shows a perspective view of an exemplaryimpactor (28) of the present invention. FIG. 6 shows a sectional view ofimpactor (28) of FIG. 2. FIG. 7 is an exploded view of the impactor (28)of FIGS. 5 and 6, wherein components of the device are spatiallyseparated for clarity. FIG. 8 shows a perspective view of impactor (28)of the present invention.

In the embodiment of particle counting or sampling device (12)illustrated in FIGS. 5-8, impactor (28) includes a base (52) portion, adispensing portion (47) and a protective portion (49). Furthermore,impactor (28) as a whole is disposable or usable for a single samplingof the air to be sampled and/or analyzed. In particular, base (52)comprises a support (53) suitable for accommodating a growth (e.g.,culture) medium (72) for the growth of microorganisms. Preferably, saidsupport (53) may be a Petri dish. In a preferred embodiment of thepresent invention, the support (53) has a height h and an area A smallerthan the height h1 and the area A1 of the base (52).

Purely by way of example and not limitation, the height h of support(53) has a value of between 17 mm and 19 mm, and the area A of saidsupport (53) has a value of between 5,930 mm2 and 5,940 mm2.Furthermore, the height h1 of the base (52) may have a value of between22 mm and 24 mm, and the area A1 of base (52) may have a value ofbetween 10,730 mm2 and 10,760 mm2.

As indicated above, support (53) is adapted to receive growth medium(72) suitable for growth of microorganisms, for example, when impactor(28) is placed in conditions of temperature and O2/CO2 favorable to thegrowth of colony-forming units (CFU). Depending on the type ofmicroorganism whose presence in the air of the environment is to beanalyzed, the technician using basic knowledge will be able to identify,among the known growth media, the one most suitable to his/her needs.Purely by way of example and not limitation, growth medium (72) can bechosen from TSA (Tryptone Soy Agar) or SDA (Sabouraud Dextrose Agar).For the purposes of the present invention, the amount of growth medium(72) present in the support (53) is such as to ensure the growth ofmicrobial colonies on medium (72). In this perspective, the support (53)is preferably adapted to receive a volume of 20-40 mL of medium. Base(52) includes, as evident from FIGS. 5-8, a conduit (51) for fluid (6),adapted to connect an interior region of base (52) with the outside,e.g., via sampling port (5). Preferably, conduit (51) is closed, forexample by means of a cap placed on its free end, when impactor (28) isnot performing sampling of fluid (6), such as during transport ofimpactor (28) or during its storage. Conversely, when impactor (28) isperforming fluid (6) sampling, conduit (51) is adapted to be connectedto a vacuum source (not shown) in such a way as to facilitate thedeposition of microorganisms present in the fluid (6) (e.g., air) sampleon growth medium (72).

Dispensing portion (47) of impactor (28) comprises one or more openings(55) to ensure the passage of airborne microorganisms onto growth medium(72). To this end, as shown in FIGS. 6 and 7, one or more openings (55)are positioned adjacent to the growth medium (72) when the dispensingportion (47) is connected to base (52). Openings (55) may have any typeof shape deemed suitable to a person skilled in the art for the purposesof the present invention. Preferably, openings (55) are rectangular inshape and distributed over the entire area (A) of support (53). In oneembodiment, openings (55) are distributed in a substantially uniformmanner over the entire area A of the support (53). As shown by way ofexample in FIGS. 5-8, this uniform distribution can be, for example, aradial pattern. A uniform arrangement of openings (55) onto growthmedium (72) is particularly advantageous since it allows theidentification of the presence of possible false positives during theevaluation phase of the air sample contamination, e.g., where amicroorganism is not uniformly distributed and detected across growthmedium (72).

As indicated above, impactor (28) operates in a similar manner toimpactors for microbial air sampling. Therefore, it is shaped in such away as to define a connection path of fluid (6) (e.g., air) between theone or more openings (55) and conduit (51). In order to ensure that thepassage of microorganisms preferably takes place only through openings(55), dispensing portion (47) and base (52) portion may be connected toeach other to seal, for example, without limitation, by means of aninterlocking mechanism.

Impactor (28) also includes a protective portion (49) that may bepositioned on dispensing portion (47) so as to occlude one or moreopenings (55), for example when impactor (28) is not performing fluid(6) sampling. In one embodiment of the present invention, protectiveportion (49), base (52) portion and/or dispensing portion (47) can bemade of transparent material. Preferably, the transparent material canbe plastic and/or glass. In the embodiment of impactor (28) in whichdispensing portion (47), protective portion (49) and/or base (52) aremade of transparent material is particularly advantageous. In fact, onceimpactor (28) is placed in temperature, O2 or CO2 conditions suitable tothe growth of microorganisms, the count and/or other characterization(s)and/or analysis of the colony-forming units (CFU) may be conductedwithout the need to remove dispensing portion (47), protective portion(49) and/or base (52) in order to access and inspect growth medium (72).Counting of colony-forming units present in growth medium (72) providesa quantitative estimate of the contamination of the fluid (6) sample andthen of, for instance, the air of the environment of interest (e.g.,environment (13)). With respect to the mode of operation of impactor(28), it operates by favoring the deposition of microorganisms presentin the fluid (6) sampled by impact of the fluid (6) passing into theopenings (55) of growth medium (72).

Impactor (28) includes a collection surface (46) configured to receiveat least a portion of particles (4) in fluid (6). In the example,particle sampling or counting device (12) (e.g., impactor (28)) includesa sampling head (48) having one or more inlets (48) for receiving atleast a portion of fluid (6) under flow. In the example, particlesampling or counting device (12) (e.g., impactor (28)) includes a base(52) operationally connected to sampling head (48) to receive at least aportion of sampled fluid (6) from sampling head (48). Base (52) includescollection surface (46), and a fluid outlet (54). In the example,sampling head (48) and base (52) are integrated components that engageto enclose collection surface (46). In the example, flow system (22) isconfigured to contact at least a portion of fluid (6) under flow withthe collection surface (46) (via sampling port (5)).

In an example, sampling head (48) and base (52) engage to entirelyenclose collection surface (46). Sampling head (48) and base (52) mayengage via a substantially airtight seal (56). Sampling head (48) andbase (52) may each independently be formed of a polymer material. Atleast a portion of base (52), sampling head (48), or both may beoptically transparent. Base (52) may have a plurality of grooves (58)provided on an outer surface (60) of base (52) to allow for effectivehandling of particle sampling or counting device (12) (e.g., impactor(28)) by robotic manipulator (20). Base (52) may have one or morefeatures to allow for effective stacking and/or unstacking of aplurality of particle sampling or counting devices (12) (e.g., aplurality of impactors (28)), including, for example and withoutlimitation, by robotic manipulator (20). Any of the particle sampling orcounting devices (12) describe herein may be a single use particlecounting or sampling device (12).

FIG. 9 is a flowchart of an example of method (2) for sampling particles(4) from a fluid (6) in accordance with yet another embodiment of thedisclosure. In the example, flowing step (14) of method (2) includescontacting (62) at least a portion of the fluid (6) with the collectionsurface (46). Providing step (10) of method (2) includes engaging (64)sampling head (48) and base (52) to entirely enclose collection surface(46) of particle sampling or counting device (12) (e.g., impactor (28)).Engaging step (64) may include sealing (66) sampling head (48) and base(52) engage via substantially airtight seal (56). Providing step (10) ofmethod (2) may include stacking (68) and/or unstacking (70) particlesampling or counting devices (12). Referring again to FIG. 4, in method(2), for the step of sterilizing (36) particle sampling or countingdevice (12) in method (2), the collection surface (46) remains enclosedduring sterilization.

Systems for Detection and Characterization of Biological Particles

In an example, in system (8), collection surface (46) of particlesampling or counting device (12) (e.g., impactor (28)) of system (8)includes a growth medium (72) for receiving biological particles (4) inthe fluid (6) under flow. In the example, system configured for roboticcontrol (18) (e.g., robotic manipulator (20)) includes an opticaldetector (74) for detecting biological particles (4) in or on growthmedium (72). In another example, system configured for robotic control(18) includes an imaging device (76) for detecting biological particles(4) in or on growth medium (72). In yet another example, systemconfigured for robotic control (18) includes optical detector (74) andimaging device (76) for detecting biological particles (4) in or ongrowth medium (72).

In the example, robot controller (24) is configured to direct movements(25) of the robotic manipulator (20) for exposing particle sampling orcounting device (12) (e.g., impactor (28)) and/or collection surface(46) to fluid (6). Robot controller (24) is configured to directmovements (25) of robotic manipulator (20) to collect particles (4) fromparticle sampling or counting device (12) (e.g., impactor (28)) and/orcollection surface (46). Robot controller (24) is further configured todirect movements (25) of robotic manipulator (20) to sample particles(4) from fluid (6) in the absence of a user (78) physically contactingparticle sampling or counting device (12) (e.g., impactor (28)).

In the example, particle sampling or counting device (12) (e.g.,impactor (28)) and/or collection surface (46) includes growth medium(72) for receiving biological particles (4) in fluid (6). Robotcontroller (24) is configured to direct movements (25) of the roboticmanipulator (20) for transporting particle sampling or counting device(12) (e.g., impactor (28)) to sterilization system (38) in a fullyassembled configuration for sterilizing particle sampling or countingdevice (12). Growth medium (72) is present within particle sampling orcounting device (12) during sterilization thereof.

FIG. 10 is a flowchart of an example of method (2) for samplingparticles (4) from a fluid (6) in accordance with still anotherembodiment of the disclosure. In the example, method (2) includesculturing (80) at least a portion of biological particles (4) receivedby growth medium (72). The culturing step (80) enables and allows foroptical detection of grown biological particles (4) (e.g., by opticaldetector (74) and/or imaging device (76)). In the example, culturingstep (80) may be carried out without disassembling the fully assembledparticle sampling or counting device (12).

In the example, method (2) includes characterizing (82) at least aportion of the grown biological particles (4) by at least one of:visualization (e.g., by user (78)), optical detection (e.g., by opticaldetector (74)), imaging (e.g., by imaging device (76)), andpolymerization chain reaction (PCR). In the example, the steps ofculturing (80), characterizing (82), or both may be carried out by thesystem configured for robotic control (18) (e.g., robotic manipulator(20)). In the example, method (2) includes determining (84) at least oneof: a presence of, a viability of, and an identity of microorganisms inthe grown biological particles (4). In the example, the determining (84)step may be carried out by the system configured for robotic control(18).

Referring to FIG. 4, the sterilizing step (36) of method (2) includessterilizing (36) particle sampling or counting device (12) (e.g.,impactor (28)) in a fully assembled configuration and with collectionsurface (46) remaining enclosed by sampling head (48) and base (52)during sterilization. In this example, the sterilizing step (36) may beperformed by treating the fully assembled and enclosed particle samplingor counting device (12) with at least one of: vaporized hydrogenperoxide, chlorine dioxide, ethylene dioxide, moist heat, dry heat, andradiation.

Robotic Control and Positioning

In an example, robot controller (24) of system (8) is configured todirect movements (25) of the robotic manipulator (20) to connect theparticle sampling or counting device (12) to the flow system (22) (e.g.,via sampling port (5)). In the example, particle sampling or countingdevice (12) (e.g., impactor (28)) includes inlet (50) for receiving atleast a portion of fluid (6) under flow. Robot controller (24) isconfigured to direct movements (25) of robotic manipulator (20) to openinlet (50) to allow for fluid (6) flow into particle sampling orcounting device (12).

In the example, particle sampling or counting device (12) includes acover (86) for enclosing particle counting or sampling device (12).Robot controller (24) is configured to direct movements (25) of roboticmanipulator (20) to remove cover (86) to allow for fluid (6) to contactparticle sampling or counting device (12). In the example, robotcontroller (24) is configured to direct movements (25) of roboticmanipulator (20) to close inlet (50) to stop fluid (6) flow intoparticle sampling or counting device (12). Robot controller (24) isconfigured to direct movements (25) of robotic manipulator (20) toreplace cover (86) to stop fluid (6) from contacting particle samplingor counting device (12).

FIG. 11 is a flowchart of an example of method (2) for samplingparticles (4) from a fluid (6) in accordance with yet another embodimentof the disclosure. In the example, the providing step (10) of method (2)includes exposing (88) particle sampling or counting device (12) tofluid (6) using system configured for robotic control (18) (e.g.,robotic manipulator (20)). In the example, the flowing step (14)includes regulating (90) (e.g., via regulating-valve (3)) a flow rate offluid (6) (e.g., into device (12) via inlet (50)) by system configuredfor robotic control (18) (e.g., robotic manipulator (20)).

In the example, method (2) includes removing (92) cover (86) of particlesampling or counting device (12) by system configured for roboticcontrol (18) (e.g., robotic manipulator (20)). Method (2) includesopening (94) inlet (50) of particle counting or sampling device (12) bysystem configured for robotic control (18) (e.g., robotic manipulator(20)). Method (2) includes connecting (96) particle sampling or countingdevice (12) to flow system (22) to allow for flowing fluid (6) by thesystem configured for robotic control (18) (e.g., robotic manipulator(20)).

In the example, method (2) includes replacing (98) cover (86) ofparticle sampling or counting device (12) by system configured forrobotic control (18) (e.g., robotic manipulator (20)). Method (2)includes closing (100) inlet (50) of particle counting or samplingdevice (12) by system configured for robotic control (18). Method (2)includes disconnecting (102) particle sampling or counting device (12)from flow system (22) to stop flow of fluid (6) by system configured forrobotic control (18) (e.g., robotic manipulator (20)).

Particle Collection and Characterization

FIG. 12 is a flowchart of an example of method (2) for samplingparticles (4) from a fluid (6) in accordance with still anotherembodiment of the disclosure. In the example, method (2) includescollecting (104) at least a portion of particles (4) received byparticle sampling or counting device (12) and/or the collection surface(46). In the example, collecting step (104) is performed by systemconfigured for robotic control (18) (e.g., robotic manipulator (20)). Inthis example, system configured for robotic control (18) includesimaging device (76).

In the example, method (2) includes a characterizing step (106)particles (4) performed by imaging device (76). The step ofcharacterizing (106) may include determining (108) a chemicalcomposition of particles (4). The step of characterizing (106) mayinclude determining (110) a particle size distribution of particles (4).

In an example, method (2) includes a synchronizing step (107). Forexample, based on a user (78)-predetermined schedule, system (8)performs synchronized sampling of fluid (6) by robotic manipulator (20)for particles (4) based on the specific cycle (mode) that is beingperformed in environment (13) (e.g., filling vials, capping vials, amongothers, in a pharmaceutical manufacturing facility). Any of the steps inany of the embodiments of method (2) disclosed herein may besynchronized in like manner.

Absence of User Interaction

In an example, flow system (22) of system (8) is integrated within acleanroom or aseptic environment (13). In the example, robot controller(24) is configured to direct movements (25) of robotic manipulator (20)to sample particles (4) from fluid (6) under flow in the absence of auser (78) being physically present in cleanroom or aseptic environment(13). In the example, robotic manipulator (20) is located inside of thecleanroom or aseptic environment (13) and the robot controller (24) islocated outside of the cleanroom or aseptic environment (13).Alternatively, robotic manipulator (20) and robot controller (24) areboth located inside cleanroom or aseptic environment (13). In theexample, fluid (6) originates in cleanroom or aseptic environment (13).Fluid (6) terminates in cleanroom or aseptic environment (13).Alternatively, fluid (6) originates in cleanroom or aseptic environment(13) and fluid (6) terminates outside cleanroom or aseptic environment(13). In another example, fluid (6) originates outside cleanroom oraseptic environment (13) and fluid (6) terminates inside cleanroom oraseptic environment (13).

FIG. 13 is a flowchart of an example of method (2) for samplingparticles (4) from a fluid (6) in accordance with still anotherembodiment of the disclosure. In the example, method (2) is performed inthe absence (114) of user (78) physically contacting particle samplingor counting device (12). In the example, method (2) may be performed inthe absence (116) of user (78) being physically present in cleanroom oraseptic environment (13). Alternatively, method (2) may be performed inthe absence (114) of user (78) physically contacting particle samplingor counting device (12) and in the absence (116) of user (78) beingphysically present in cleanroom or aseptic environment (13).

Example 2—Robotically Controlled Optical Particle Counter

The systems and methods described herein may incorporate an opticalparticle counter systems used in conjunction with robotic controlsystems, for example, to position the optical particle counter toreceive fluid in order to characterize the fluid, including determiningnumber, size or other characteristics of the particles contained in thefluid.

Optical particle counters are known in the art, for example, in U.S.Pat. No. 7,745,469, U.S. Pat. No. 7,916,29 and U.S. Pat. No. 8,154,724,which are each incorporated by reference in their entirety andspecifically with regard to optical particle detection systems andmethods.

FIG. 14 provides an example of an optical particle counter system. Fluidflows through a flow system 150 into a flow chamber 210. An opticalsource 220 projects a beam of electromagnetic radiation 221 (e.g., alaser) into the flow chamber 210, where the electromagnetic radiation221 interacts with any particles in the fluid. The electromagneticradiation 221 is then collected by a collection system 230 and directedtowards a photodetector 240 which generates an electric signalcharacteristic of the number and/or size of particles being detected. Insome embodiments, a processor or analyzer 100 may be operable connectedto the particle detection system.

STATEMENTS REGARDING INCORPORATION BY REFERENCE AND VARIATIONS

All references throughout this application, for example patent documentsincluding issued or granted patents or equivalents; patent applicationpublications; and non-patent literature documents or other sourcematerial; are hereby incorporated by reference herein in theirentireties, as though individually incorporated by reference, to theextent each reference is not inconsistent with the disclosure in thisapplication (for example, a reference that is partially inconsistent isincorporated by reference except for the partially inconsistent portionof the reference).

The terms and expressions which have been employed herein are used asterms of description and not of limitation, and there is no intention inthe use of such terms and expressions of excluding any equivalents ofthe features shown and described or portions thereof, but it isrecognized that various modifications are possible within the scope ofthe invention claimed. Thus, it should be understood that although thepresent invention has been specifically disclosed by preferredembodiments, exemplary embodiments and optional features, modificationand variation of the concepts herein disclosed may be resorted to bythose skilled in the art, and that such modifications and variations areconsidered to be within the scope of this invention as defined by theappended claims. The specific embodiments provided herein are examplesof useful embodiments of the present invention and it will be apparentto one skilled in the art that the present invention may be carried outusing a large number of variations of the devices, device components,methods steps set forth in the present description. As will be obviousto one of skill in the art, methods and devices useful for the presentmethods can include a large number of optional composition andprocessing elements and steps.

As used herein and in the appended claims, the singular forms “a”, “an”,and “the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, reference to “a cell” includes a pluralityof such cells and equivalents thereof known to those skilled in the art.As well, the terms “a” (or “an”), “one or more” and “at least one” canbe used interchangeably herein. It is also to be noted that the terms“comprising”, “including”, and “having” can be used interchangeably. Theexpression “of any of claims XX-YY” (wherein XX and YY refer to claimnumbers) is intended to provide a multiple dependent claim in thealternative form, and in some embodiments is interchangeable with theexpression “as in any one of claims XX-YY.”

Every device, system, combination of components, or method described orexemplified herein can be used to practice the invention, unlessotherwise stated.

Whenever a range is given in the specification, for example, atemperature range, a time range, or a composition or concentrationrange, all intermediate ranges and subranges, as well as all individualvalues included in the ranges given are intended to be included in thedisclosure. It will be understood that any subranges or individualvalues in a range or subrange that are included in the descriptionherein can be excluded from the claims herein.

All patents and publications mentioned in the specification areindicative of the levels of skill of those skilled in the art to whichthe invention pertains. References cited herein are incorporated byreference herein in their entirety to indicate the state of the art asof their publication or filing date and it is intended that thisinformation can be employed herein, if needed, to exclude specificembodiments that are in the prior art. For example, when composition ofmatter are claimed, it should be understood that compounds known andavailable in the art prior to Applicant's invention, including compoundsfor which an enabling disclosure is provided in the references citedherein, are not intended to be included in the composition of matterclaims herein.

As used herein, “comprising” is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps. As usedherein, “consisting of” excludes any element, step, or ingredient notspecified in the claim element. As used herein, “consisting essentiallyof” does not exclude materials or steps that do not materially affectthe basic and novel characteristics of the claim. In each instanceherein any of the terms “comprising”, “consisting essentially of” and“consisting of” may be replaced with either of the other two terms. Theinvention illustratively described herein suitably may be practiced inthe absence of any element or elements, limitation or limitations whichis not specifically disclosed herein.

One of ordinary skill in the art will appreciate that devices, systems,and methods other than those specifically exemplified can be employed inthe practice of the invention without resort to undue experimentation.All art-known functional equivalents, of any such devices and methodsare intended to be included in this invention. The terms and expressionswhich have been employed are used as terms of description and not oflimitation, and there is no intention that in the use of such terms andexpressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the invention claimed.Thus, it should be understood that although the present invention hasbeen specifically disclosed by preferred embodiments and optionalfeatures, modification and variation of the concepts herein disclosedmay be resorted to by those skilled in the art, and that suchmodifications and variations are considered to be within the scope ofthis invention as defined by the appended claims.

We claim:
 1. A system for detecting particles in a fluid, the systemcomprising: a particle detection device comprising: an inlet forreceiving a particle-containing fluid; a sampling region for detectingparticles in the fluid, the sampling region in fluid communication withthe inlet; and an outlet for discharging the fluid, the outlet in fluidcommunication with the sampling region; a sterilization system forsterilizing all or part of the particle detection device; and a roboticmanipulator system configured to perform at least one of the followingsteps: transport the particle detection device to the sampling location;remove the particle detection device from the sampling location; andregulate a flow of fluid through the particle detection device; andwherein the robotic manipulator system is configured to transport theparticle detection device to the sterilization system.
 2. The system ofclaim 1, wherein the particle detection device is an optical particlecounter.
 3. The system of claim 2, wherein the optical particle counteris a scattered light particle counter, a light extinction opticalparticle counter or a fluorescent optical particle counter.
 4. Thesystem of claim 1, wherein the particle detection device is an impingeror a sampling cyclone.
 5. The system of claim 1 comprising a flow systemfor flowing the fluid through the particle detection device.
 6. Thesystem of claim 5, wherein the robotic manipulator system is configuredto connect the particle detection device to the flow system.
 7. Thesystem of claim 5, wherein the flow system is located within a cleanroomor aseptic environment, and wherein the robotic manipulator system isconfigured to sample the particles from the fluid in the absence of auser being physically present in the cleanroom or aseptic environment.8. The system of claim 7, wherein the robotic manipulator system islocated inside of the cleanroom or aseptic environment.
 9. The system ofclaim 1, wherein the particle detection device is an impactor.
 10. Thesystem of claim 9, wherein the impactor comprises an impactor basehaving a plurality of grooves provided on an outer surface to interfacewith a working end of the robotic manipulator system.
 11. The system ofclaim 9, wherein at least a portion of the impactor is transparent. 12.The system of claim 9, wherein the impactor includes a collectionsurface comprising a growth medium for receiving biological particles inthe fluid; wherein the robotic manipulator system is configured fortransporting the impactor to the sterilization system in a fullyassembled configuration for sterilizing the impactor; and wherein thegrowth medium is present within the impactor during sterilizationthereof.
 13. The system of claim 1, wherein the sterilization systemutilizes vaporized hydrogen peroxide, chlorine dioxide, ethylene oxide,moist heat or dry heat to sterilize the particle detection device. 14.The system of claim 1, wherein the robotic manipulator system comprisesan optical detector or an imaging device.
 15. The system of claim 1,wherein the robotic manipulator system is configured to expose the inletof the particle detection device to the fluid.
 16. The system of claim1, wherein the robotic manipulator system is configured to collectparticles from the particle detection device.
 17. The system of claim 1,wherein the robotic manipulator system is configured to operate theparticle detection device in the absence of physical contact of theparticle detection device by a user.
 18. The system of claim 1, whereinthe robotic manipulator system is configured to open the inlet to allowfor fluid flow into the particle detection device.
 19. The system ofclaim 1, wherein the particle detection device comprises a cover forenclosing the inlet; and wherein the robotic manipulator system isconfigured to remove the cover to allow for fluid to enter the inlet.20. The system of claim 19, wherein the robotic manipulator system isconfigured to replace the cover to stop the fluid from entering theinlet.
 21. The system of claim 1, wherein the robotic manipulator systemis configured to close the inlet to stop fluid flow into the particledetection device.
 22. A method for detecting particles in a fluid, themethod comprising the steps of: exposing the inlet of a particledetection device to a particle-containing fluid; flowing theparticle-containing fluid into the inlet; directing the fluid through asampling region of the device; discharging the fluid through an outletof the device; wherein the exposing step and/or the flowing step isperformed by a robotic manipulator system; and sterilizing the particledetection device via the robotic manipulator system.
 23. The method ofclaim 22, wherein particle detection device comprises an impactor, andwherein the sterilizing step comprises sterilizing the impactor in afully assembled configuration.
 24. The method of claim 23, wherein acollection surface of the impactor remains enclosed duringsterilization.
 25. The method of claim 23, wherein the sterilizing stepcomprises treating the impactor with vaporized hydrogen peroxide. 26.The method of claim 25 comprising: determining a viability, an identityor both of microorganisms in the cultured biological particles.
 27. Themethod of claim 26, wherein the determining step is performed by therobotic manipulator system.
 28. The method of claim 23, wherein at leastsome of the particles are biological particles, comprising: culturing atleast a portion of the biological particles received by the impactor,wherein the culturing occurs inside the fully assembled impactor. 29.The method of claim 28 comprising: optically detecting culturedbiological particles via the robotic manipulator system.
 30. The methodof claim 29 comprising: characterizing the cultured biological particlesvia optical detection or imaging performed by the robotic manipulatorsystem.
 31. The method of claim 30 wherein the robotic manipulatorsystem comprises an imaging device; and wherein the characterizing stepis performed via the imaging device.
 32. The method of claim 23, whereinthe impactor is a single-use device.
 33. The method of claim 22,comprising: transporting the particle detection device, via the roboticmanipulator system, to a sterilization location for the sterilizingstep.
 34. The method of claim 22 comprising: after the sterilizing step,transporting the particle detection device, via the robotic manipulatorsystem, to a sampling location.
 35. The method of claim 22, wherein theflowing step comprises regulating a flow rate of the fluid via therobotic manipulator system.
 36. The method of claim 22 comprising: priorto the flowing step, connecting the particle detector to a flow system.37. The method of claim 22 comprising: collecting at least a portion ofthe particles that flow into the inlet.
 38. The method of claim 37,wherein the collecting step is performed by the robotic manipulatorsystem.
 39. The method of claim 22, wherein the fluid originates and/orterminates in a cleanroom or aseptic environment; and wherein the methodis performed in the absence of a user being physically present in thecleanroom or aseptic environment.
 40. The method of claim 22, whereinthe exposing step and the flowing step are performed by the roboticmanipulator system.